Project Summary: Neurological disorders such as epilepsy and memory loss that develop several years after traumatic brain injury are a major source of physical disability and economic burden after brain trauma. The time window between the initial insult and the disease suggest that progressive changes that occur after brain injury underlie neurological disease and that early interventions might prevent these debilitating outcomes. The hippocampal dentate gyrus is the major focus of neuronal damage and increased excitability after concussive brain injury and in post-traumatic temporal lobe epilepsy. Apart from injuring neurons, traumatic release of endogenous molecules from disrupted cells and extracellular matrix can activate pattern-recognition receptors of the innate immune system including Toll-like receptors. Certain TLR subtypes, including TLR4 are expressed in neurons and regulate neurogenesis and cell death. The central hypothesis of this proposal is that, early post-injury increase in activation of neuronal TLR4 alters excitability and leads to excitotoxic damage of specific dentate neuronal types and facilitating acute and chronic increases in network excitability. Using the rodent fluid percussion injury model of concussive brain trauma and current physiological techniques, Aim 1 will distinguish the cellular, signaling and channel mechanisms underlying TLR4 modulation of neuronal excitability in the normal brain and early after brain injury. Aim 2 will determine whether TLR4 activation in specific interneuronal populations contributes to excitotoxic injury and loss of certain interneuronal subtypes. Finally, Aim 3 will use a combination of histological, physiological and behavioral assays to test whether selective TLR4 antagonists reduce long-term susceptibility to epilepsy and memory deficits after brain injury. It is anticipated that the proposed studies will identify novel roles for perturbed TLR4 signaling in post-traumatic pathology and generate strategies for targeted treatment to improve the long-term neurological outcome after traumatic brain injury while preserving normal physiology. Such preventive strategies will greatly improve the quality of life of patients after brain injury and, in keeping with the NINDS mission, decrease the burden that post-traumatic neurological diseases place on the health care system.